Glaucoma is a leading cause of irreversible vision loss worldwide. Glaucoma is an optic neuropathy with age and increased intraocular pressure (IOP) as the two main risk factors for development of vision loss. An inbred mouse strain (DBA2/J) has been identified which spontaneously develops increased IOP and optic nerve damage as the mice age, similar to the chronic, progressive course of human glaucomatous disease. In this career training grant application, we will use the DBA2/J glaucoma model to identify molecular and cellular mechanisms of glaucoma. We will test the hypothesis that the retinal ganglion cell-specific transcription factor brn-3b is specifically down-regulated by raised intraocular pressure that induces RGC death. The demonstration that brn-3b plays a functionally important role in glaucoma will provide a molecular target for neuroprotective strategies with which to treat human glaucoma. Specific Aim A will correlate the cellular, molecular, and functional changes in the retina as glaucoma progresses in the DBA2/J mouse model of glaucoma. This aim will determine the structure-function correlation between the brn-3b and retinal ganglion cells with visual function in glaucoma. Specific Aim B will determine if down-regulation of the retinal ganglion cell-specific transcription factor brn-3b is functionally associated with raised intraocular pressure and the development of glaucoma in in vivo models. Specific Aim C will determine if brn-3b is neuroprotective for retinal ganglion cells by over expressing brn-3b in RGC and determining if brn-3b is anti-apoptotic in RGC cell culture and in vivo systems. This grant's specific aims will characterize a popular animal model of glaucoma, lead to important discoveries in our understanding of glaucoma, and develop the career of the principal investigator as a clinician scientist.